Estradiol-TTS having water-binding additives

ABSTRACT

A transdermal therapeutic system comprising the active substance estradiol and having a layered structure of a backing layer which is impermeable to active substances and moisture, and active substance-containing matrix, and, if necessary, a removable protective layer covering the matrix, is characterized by the fact that the matrix comprises glycerol either comprising a maximum of 1%-wt. of water or being substantially free from water.

The present invention relates to a transdermal therapeutic systemcomprising the active substance estradiol and having a layered structureof a backing layer which is impermeable to active substances andmoisture, an active substance-containing matrix, and, if necessary, aremovable protective layer covering the matrix.

BACKGROUND OF THE INVENTION

In the therapy of several diseases, Transdermal Therapeutic Systems(TTS) have been introduced on the market for some time now.

Also, TTSs comprising the active substance estradiol have been on themarket as therapeutic agents for climacteric complaints, and, since ashort time ago, also against osteoporosis; they have proved successfulin therapy.

In the following the term "estradiol" is to be understood as theanhydrous substance of 17-β-estradiol.

A disadvantage of prior art systems is the insufficient capability ofthe active substance to permeate through the skin. This cannot beincreased beyond a certain limit, the so-called "saturation flow",although several galenic measures with respect to the TTS-design havebeen taken (use of multilayer systems, use of controlling membranes,variation of the active substance concentration, modification of thebase polymer, and the like). This finding that the transdermal flow ofan active substance from the solid, finely dispersed phase cannot beincreased further in principle, can already be found in the stilltrailblazing works of Higuchi (e.g., T. Higuchi; Physical ChemicalAnalysis of percutaneous absorption process from creams and ointments.J. Soc. Cosmetic Chem. 11, p. 85-97 (1990).

The systems described in EP 0 421 454 comprise estradiol in an acrylicpolymer under addition of "crystallization inhibitors" and tackifyingresins. Swelling agents are contained to give protection againstpremature loss of adhesive force.

In addition, with a lot of active substances, so-called "enhancers" canbe added to the TTS during production. These are usually liquidadmixtures improving the absorption properties of human skin; for thisreason, they allow the absorption of the active substance from asufficiently small TTS-surface.

Readily volatile enhancers, e.g., ethanol used for the active substanceestradiol, particularly involve problems caused by an extreme softeningof the TTSs' adhesive layers, and they require additional bulkycompartments in the system, rendering the TTS unacceptably thick.

The addition of less volatile, however, mostly less active enhancers(e.g., glycerol esters, cyclic amides, eucalyptol) allows the productionof matrix systems comprising active substances and anabsorption-promoting component in one or several layers. However, theinsufficient adhesive force of these TTSs is disadvantageous. U.S. Pat.No. 4 863 738 represents one of many examples claiming the applicationof active substances, e.g., estradiol, together with a certain enhancer(in this case glycerol monooleate) in an optional TTS-matrix and in anoptional concentration.

However, even such a prior art TTS does not permit a satisfactorytherapy either. The reason is that either the chosen enhancers arepoorly tolerated by the skin or that the systems have unacceptably largesurfaces owing to the still insufficient flow through the skin.

Another (theoretic) possibility of increasing the active substance flowthrough the skin is to dissolve more active substance molecularlydisperse, i.e., crystal-free, in the TTS than corresponds to thesaturation solubility. The permeation rate through the skin increases tothe same extent as the degree of supersaturation of these systems.However, these physical states are thermodynamically unstable, thereforethese forms of administration are not storable. Within some months oryears, at the latest, a spontaneous unforeseeable precipitation ofactive substance will take place so that the flow rate through the skingradually decreases to the saturation flow level; depending on thestarting concentration, this results in losing a great portion of theinitial therapeutic activity.

This process occurring during storage is due to particularphysicochemical characteristic features of estradiol.

At room temperature and normal relative air humidity (20-60% relativehumidity), estradiol is not present in one of the two known anhydricmodifications (I and II) but as a semihydrate (Busetta, Acta Cryst.1972, B28, 560). Owing to the layered structure stabilized via hydrogenbridges, and because of the diffusional compactness of the crystalcompound, the hydrate can be subjected to a short-term heat treatment totemperatures of about 170° C. without decomposition thereof(Kuhnert-Brandstatter and Winkler (1976) Scientia Pharmaceutica 44 (3),177-190). However, estradiol-semihydrate can quantitatively be convertedinto the anhydrous form already at about 120° C. by way of enlarging thecrystal surface by means of micronizing. According to the inventors'observations, the transformation already takes place at about 90° C. ifheating is conducted slowly (0.2-1 K/min) and in case of a particularlyfine substance.

With decreasing partial water vapor pressure, on the other hand,estradiol has a higher solubility in some polymers, particularly inpolyacrylates. According to Fick's law, higher concentrations withotherwise same conditions increase the diffusion flow through the skin;for this reason such a concentration increase is very desirable intransdermal therapeutic systems. However, the water introduced with theestradiol-semihydrate is already sufficient to cause gradualrecrystallization from the solution as estradiol-semihydrate(Kuhnert-Brandstatter and Winkler (1976) Scientia Pharmaceutica 44 (3),177-190). During crystallization, the flow rate from the system to theskin considerably decreases with the diminishing concentration.

Accordingly, transdermal therapeutic systems are known that offer apharmacotherapeutically satisfying solution by exactly regulating theconcentration to below the saturation solubility of theestradiol-anhydrate (DE-PS 42 37 453) or by using partially undissolved,disperse estradiol-anhydrate (DE-PS 42 23 360). Even in consideration ofthis latest state of the art, it is important to maintain a sufficientlylow atmospheric humidity during production and storage of anestradiol-TTS in order to avoid large-area precipitation of the poorlysoluble estradiol-semihydrate.

To this end, a package having a low water-vapor permeability can be usedin principle. However, owing to the small estradiol amounts contained intoday's TTSs, very small amounts of humidity are sufficient to causeprecipitation of the estradiol-semihydrate. If, for example, 2 mg ofestradiol (anhydrous) are present in a TTS in dissolved form, an amount(calculated on the basis of the molecular-weight ratios) of only 66.1 μgof water can cause complete precipitation. Using conventional packagingmeans, it is therefore very difficult to exclude entry of such smallquantities of moisture over storage periods of several years.

DESCRIPTION OF THE INVENTION

Accordingly, it is the object of the present invention to provide atransdermal therapeutic system comprising estradiol, that comprises along-term protection against precipitation of the estradiol-semihydrate,said protection being incorporated in the active substance-containinglayers themselves, and which prevents crystallization to theestradiol-semihydrate.

Glycerol is a very polar compound and miscible with water in any ratio.Anhydrous glycerol is very hygroscopic and can be used as dehydratingagent under certain conditions. It can be demonstrated by way ofexperiments that its anhydrous form is able to remove crystal water fromthe estradiol-semihydrate. In this connection, the term "anhydrous" or"substantially anhydrous or substantially free from water" is to beunderstood as a water content of less than 1%. If estradiof-semihydrateis stirred in anhydrous glycerol at room temperature for about 24 hours,the flat-shaped crystals of the semihydrate are converted into thinneedles. These needles are either the anhydrous estradiol or anestradiol-glycerol-solvate. An addition of only 2% of water to theglycerol used for this test prevents this reaction. This clearlydemonstrates that the species resulting during the reaction withanhydrous glycerol does not comprise any water.

The above-mentioned embodiment of a TTS according to the presentinvention can be realized in different manners. The most simple form isa single-layer matrix system whose matrix simultaneously has apressure-sensitive adhesive function, rendering a special adhesive layersuperfluous. The glycerol dispersed in the matrix ensures anequilibrium-moisture content over the storage period that is low enoughto render precipitation of the estradiol-semihydrate impossible.

If the adhesive force of this layer is insufficient or if direct skincontact of this layer is to be avoided, the matrix may be laminated witha special skin adhesive layer.

If a membrane which is hardly permeable to estradiol is introducedbetween such a matrix, which comprises estradiol and water-bindingdisperse glycerol, and the adhesive layer, an active substance releaseis achieved which is controlled by the patch rather than by the skin.

In addition to the wide-spread acrylic acid copolymers suitable for theuse with estradiol, other polymers may also be used as base material,such as polyisobutylene, polyvinyl acetate and copolymers, syntheticrubber, block polymers of styrene and isoprene or of styrene andbutadiene, and silicones.

In any case, the characterizing feature of transdermal therapeuticsystems according to the present invention is the presence of disperse,substantially anhydrous glycerol. In this connection, the exact amountof glycerol in the system must be chosen such that, on the one hand, thesolubility of glycerol in the system is exceeded and that it is presentas separate phase dispersed in small droplets, and, on the other hand,that the total moisture-binding capacity in the system is sufficient. Anaddition in the range of 2 or even 1 percent may be considered asminimum amount; the upper limit is determined by mechanical values, suchas flowability of the matrix, adhesive force, and processibility. Ingeneral, a proportion of 10 to 50 percent by weight, preferably between10 and 35 percent by weight is desired.

EXAMPLES Example 1

2.0 g of 17-β-estradiol-semihydrate, micronized is mixed with

2.75 g of anhydrous glycerol,

25 g of an acrylic ester copolymer solution (solids content 42%) and

5.9 g of colophony-glycerol ester derivative (Staybelite Ester 5E, ofHercules)

and subsequently coated on a 100 μm siliconized polyester film in such amanner that the coating weight amounts to 120 g/m².

The coating is dried at.25° C., at 50° C., at 80° C. and at 95° C., eachtime for 10 minutes. A 10 μm polyester film is immediately applied(laminated) on the dry layer under roller pressure, avoiding theformation of air bubbles.

Transdermal systems of 16 cm² are obtained by punching using a wadpunch. These are immediately packed into moistureproof, heat-sealablebags.

Example 2

2.0 g of 17-β-estradiol-semihydrate, micronized,

60.0 g of Cariflex TR 1107® (styrene-isoprene block polymer),

120.0 g of Staybelite Ester 5E (thermoplastic ester gum of colophonyderivatives),

50.0 g of viscous paraffin

50.0 g of anhydrous glycerol

are rendered molten in an evacuatable kneader at 130° C. and broughtinto an externally homogeneous form by means of kneading within tenhours.

The melt is cooled down to 120° C.; in a continuous coating line it issubsequently coated onto a siliconized polyester film of 1 00 μmthickness in such a manner that the weight per unit area amounts to 200g/m².

Afterwards a polyester film 15 μm thick is applied (laminated) underroll pressure on the still hot layer, avoiding the formation of airbubbles.

Transdermal systems of 16 cm² are obtained by punching using a wadpunch.

We claim:
 1. A storage stable transdermal therapeutic system comprisingthe active substance estradiol and having a layered structure of abacking layer which is impermeable to active substances and moisture, anactive substance-containing matrix, wherein the matrix comprises atleast 2% by weight of glycerol that has a maximum of 1%-wt. of water oris substantially free from water, said amount of said glycerol providingprotection against precipitation of estriol semihydrate during storage.2. A transdermal therapeutic system according to claim 1, wherein thematrix consists of several layers at least one layer comprising glycerolthat has a maximum of 1%-wt. of water or is substantially free fromwater.
 3. A transdermal therapeutic system according to claim 1, whereinthe estradiol contained in the matrix is present as a dispersion of ananhydrous crystallizate.
 4. A transdermal therapeutic system accordingto claim 1, wherein the base material of the matrix or of one of itslayers is an acrylic-acid ester copolymer.
 5. A transdermal therapeuticsystem according to claim 4, wherein the acrylic-acid ester copolymerhas a solubility for the crystallizate of the estradiol of between 0.4and 3.0%.
 6. A process for the production of a transdermal therapeuticsystem according to claim 1 which comprises:a) preparing a suspension ofestradiol-semihydrate and water-binding glycerol in a solution,dispersion, or melt of the matrix base material, b) coating a carrierfoil with the suspension, and c) drying the applied layer by heating to50 to 175° C. to convert estradiol-semihydrate into anhydrous estradiol.7. A process according to claim 6, wherein the resulting transdermaltherapeutic system is packed into a packaging means which can be sealedin a gas-tight manner and that a desiccant is additionally added to saidpackage.
 8. A transdermal therapeutic system according to claim 1, whichcontains in addition a removable protective layer covering the matrix.9. A transdermal therapeutic system according to claim 1, wherein thematrix comprises between 10 and 50% by weight of glycerol that has amaximum of 1% wt, of water or is substantially free from water.
 10. Atransdermal therapeutic system according to claim 9, wherein the amountof glycerol is in the range from 10 to 35% by weight.
 11. A storagestable transdermal therapeutic system comprising the active substanceestradiol and having a layered structure of a backing layer which isimpermeable to active substances and moisture, an activesubstance-containing matrix, wherein the matrix contains at least 2% byweight of glycerol in disperse form that has a maximum of 1%-wt. ofwater or is substantially free from water.
 12. A transdermal therapeuticsystem according to claim 11, wherein the amount of glycerol exceeds itssolubility in the system and the glycerol is present as a separate phasedispersed in small droplets therein.
 13. A transdermal therapeuticsystem according to claim 11, wherein the matrix consists of severallayers at least one layer comprising glycerol that has a maximum of1%-wt. of water or is substantially free from water.
 14. A transdermaltherapeutic system according to claim 11, wherein the estradiolcontained in the matrix is present as a dispersion of an anhydrouscrystallizate.
 15. A transdermal therapeutic system according to claim11, wherein the base material of the matrix or of one of its layers isan acrylic-acid ester copolymer.
 16. A transdermal therapeutic systemaccording to claim 15, wherein the acrylic-acid ester copolymer has asolubility for the crystallizate of the estradiol of between 0.4 and3.0%.
 17. A transdermal therapeutic system according to claim 11, whichcontains in addition a removable protective layer covering the matrix.18. A transdermal therapeutic system according to claim 11, wherein thematrix comprises between 10 and 50% by weight of glycerol that has amaximum of 1%-wt. of water or is substantially free from water.
 19. Atransdermal therapeutic system according to claim 18, wherein the amountof glycerol is in the range from 10 to 35% by weight.